Download Zika virus, emergencies, uncertainty and vulnerable populations

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J R Coll Physicians Edinb 2016; 46: 3–6
http://dx.doi.org/10.4997/JRCPE.2016.102
© 2016 Royal College of Physicians of Edinburgh
clinical
Zika virus, emergencies, uncertainty and
vulnerable populations
DM Brett-Major, 2CE Roth
1
Fellow, Royal College of Physicians of Edinburgh; 2Fellow, Royal College of Pathologists
1
Keywords Flavivirus, microcephaly, outbreak, public health emergency, Zika
Declaration of Interests No conflict of interest declared
Correspondence to D Brett-Major
5902 Greentree Road
Bethesda
MD 20817-3460
USA
e-mail [email protected]
The World Health Organization (WHO) declared a
Public Health Emergency of International Concern
(PHEIC) on 1 February 2016. The press immediately
latched onto this declaration as confirmation of the
threat from the Zika virus. Interestingly, while the
Emergency Committee certainly expressed concern
regarding the virus, the emergency itself was declared on
a health outcome; increasingly observed microcephaly
cases as well as other neurologic disorders in areas
currently affected by a Zika virus outbreak. Briefly
reviewing this virus’ story helps us to appreciate these
distinctions and what they portend regarding what is
known and not yet known about the Zika virus and
these outbreaks, what is important and the ways
responders and scientists will try to move forward.
The Zika virus was first described in the 1950s in
Transactions of the Royal Society for Tropical Medicine and
Hygiene. An experienced team of UK and US
investigators, who worked on identifying and
characterising mosquito-vectored viruses in Africa,
identified the virus in Zika, Uganda.1,2 Working on six
tree platforms in the forest separated from Lake
Victoria by swamp, placed there to optimize sylvatic
yellow fever virus work, the team took a blood sample
from a febrile Rhesus monkey in April 1947. Dick et al.
describe rapidly cultivating the virus in mice, how it
prospered only after intracerebral inoculation and was
a filterable agent. In a month the team demonstrated
that it could be neutralised by sera from the monkey
that had originally been ill, Rhesus 766. Eight months
later, again working on yellow fever virus, the team
isolated the Zika virus from a collection of Aedes
africanus (Theobold) mosquitos captured from the
same platforms. Filtrate from the mosquitoes made
another Rhesus monkey febrile and gave mice
encephalitis. That monkey’s sera could neutralise the
filterable agents from when it was sick, the mice and
Rhesus 766. The team then challenged the Zika virus
against dengue and yellow fever virus immune sera, as
well as dengue and yellow fever viruses against Zika
virus immune serum. They did not substantially crossreact. A long list of known viruses was brought through
the same drill with similar results.
Many mice paid dearly for the team’s burgeoning
knowledge of the Zika virus, usually with encephalitis and
death, sometimes with other neuropathic effects such as
motor limb weakness. When the team attempted to
assess how monkeys fare with intracerebral inoculation of
the virus, as had been done to the mice, they were faced
with protective sera in their captive monkeys. This gave
them the idea to assess whether people from the area
had protective sera against Zika virus. Taking advantage of
a sera repository designed for yellow fever virus work,
they found highly protective sera in 20% of samples from
Bwamba and nearly 10% of those from the West Nile,
though none in Zika or Kampala.
Despite a 69-year awareness of the virus, Zika as a search
term yields only just over 300 citations indexed in
MEDLINE, several of them recently published. Contrast
this with chikugunya virus, also discovered and
characterised in this early rise of virology and with some
similar holistic features, which has 2,627 indexed
publications. Perhaps this is because the Zika virus’ clinical
appearance has been limited and more mild, and observed
because of sporadic human cases in Africa and Asia.3 In
2007, a Micronesian outbreak resulted in an estimated 7
of 10 child and adult residents becoming infected.4
Despite this astounding attack rate and mild increase in
detection with post-outbreak observation in other areas
of Asia, subsequent literature remained relatively sparse.
Since its emergence in Brazil in May 2015, it has spread
across over 20 countries in the Americas.5
The virus’ success in the New World is no surprise.
Like Africa and Asia, the Americas continue to
experience extensive dengue and now chikungunya
virus transmission from the same cross-over species of
mosquitoes that yellow fever virus exploits in its
endemic areas when breaking free of its sylvatic cycle
3
clinical
DM Brett-Major, CE Roth
table 1 Reported clinical characteristics of confirmed Zika virus infections in previous outbreaks
Country
Nigeria
Year
1952
Indonesia
1977–78
Yap Island,
Federated States
of Micronesia
2007
French Polynesia
2013–14
Thailand
2012–14
Brazil (Bahia)
2015
Brazil (Natal)
2015
Cases Description and comment
3
All patients experienced mild to moderate illness with fever – a 30-year-old man
with arthralgia and cough though no other pulmonary findings, a 10-year-old girl
with headache and a 24-year-old man with arthralgia, headache, retro-orbital pain
and loose stools. The clinical course for each spanned weeks.9
7
In this study of in-patients with acute fever, 7 patients were shown to have acute and
convalescent sera responses to Zika virus near the end of a wet season. In addition to
fever, these patients experienced abdominal discomfort, anorexia and ‘dizziness’10
49
There were an additional 59 probable cases reported. 31 of the 49 confirmed cases
were clinically characterised: rash (28), fever (20), arthralgia (20), conjunctivitis (17,
non-purulent), myalgia (15), headache (14), retro-orbital pain (12), oedema (6),
vomiting (3). A linked retrospective household and entomologic survey estimated that
nearly 3 in 4 residents were infected, 900+ of those (approximately 1 in 4–5) had a
consistent clinical illness.4
8,723 Among more than 8,000 reported confirmed and suspected patients meeting a case
definition of rash or fever with two additional symptoms (conjunctivitis, arthralgia or
myalgia, oedema), with an estimated case burden exceeding 30,000 patients, authorities
reported a total of 73 patients with neurologic and auto-immune complications. This
included Guillain-Barré Syndrome (43), meningo-encephalitis (15), other neurologic
complications such as paraesthesia, facial paralysis, and myelitis (23), immuneassociated thrombocytopenia (8), ophthalmologic disorders (2) and at least one
cardiac complication.12,13
7
Clinical information was available for 5 of the patients captured in this national,
serology-based case finding activity; 4 women and 1 man ranging from 12–39 years old,
their signs and symptoms included fever (5), rash (5), arthralgia (2), conjunctivitis (2),
sore throat (2), headache (1), myalgia (1), rhinorrhoea (1). All of the patients had mild
clinical courses.7
7
Researchers validated the diagnosis of a small cluster of cases from a single hospital.
Among 6 women and 1 man, they experienced fever (3), rash (6), myalgia (4), headache
(3). While they did not list arthralgia or conjunctivitis among these confirmed cases,
the authors said that the outbreak triggering this work was one of ‘an illness
characterised by maculopapular rash, fever, myalgia/arthralgia, and conjunctivitis.’8
8
Among 8 confirmed patients in the northeast of Brazil, 7 were women. Ranging in age
from 18–65, these patients demonstrated fever (6), rash (8), small and medium joint
arthralgia (7, 6 with arthritis), myalgia (6), retro-orbital pain (4), lymphadenopathy (3),
leukopaenia (2). Fever lasted up to 8 days and joint pain generally less than 2 weeks. 5
of the 6 patients assessed on a pain scale of 10 scored 7 or higher.11
into encroaching human populations. The Zika virus is
a member of the Flavivirus genus, and yet within that
genus has a very interesting phylogeny. In a recent,
ambitiously broad genomic characterisation of
Flaviviruses in the context of their mosquito vectors,
assessed Zika virus strains clustered closest to the
predominantly Culex carried members of the genus.6
These include some of the family most notoriously
known for neurotropism such as Japanese encephalitis,
St Louis encephalitis and West Nile viruses; insofar as
any Flavivirus is much like another in this very diverse
viral genus. After the Culex favouring group, the Zika
virus was next closest to the dengue viruses, also
carried by Aedes mosquitoes. The diversity of vector,
carrier and amplifying species that contribute to a Zika
virus outbreak is not yet known. Several Flaviviruses in
both Culex and Aedes mosquitoes are passed to
progeny through transovarial transmission, infecting
4
new generations of mosquitoes in between the
amplifying events of human outbreaks. Consequently,
the Zika virus, even in the setting of improved control, is
unlikely to leave us soon. It is worth exploring the virus’
impact in humans further.
Zika virus infection seems to have a high asymptomatic
or sub-clinical rate. When ill patients present, they seem
to do so with an influenza-like illness, frequently with
rash, which could be easily confused in care settings for
dengue or chikungunya viruses, early leptospirosis, scrub
typhus or others. Patients often have fever, as well as
variable combinations of other symptoms such as rash,
arthralgia, myalgia, conjunctivitis, headache, retro-orbital
pain and abdominal complaints.4,7,8–11 Table 1 describes
the clinical manifestations reported from previous
outbreaks. Neurologic sequelae, including Guillain-Barré
syndome, were observed in the large French Polynesia
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© 2016 RCPE
Zika virus, emergencies, uncertainty and vulnerable populations
table 2 Examples of Flaviviruses that have been
associated with neurologic syndromes
The burgeoning story of microcephaly associated with
the Zika virus outbreaks is even less clear than that of
the primary clinical syndromes. According to a Pan
American Health Organization report, by October
2015 Brazil had reported 141 cases of microcephaly
against a usually observed case count of 10 in the
context of its Zika virus epidemic.16 By November, the
total microcephaly count climbed under proactive
identification to over 1,200 cases.17 Also in November,
French Polynesia authorities reported that 17 fetal
malformations may have occurred in connection with
its 2014 Zika virus infection epidemic, 12 cerebral
malformations and five with brainstem dysfunction.18
Four of these 17 mothers were assessed for nonspecific Flavivirus exposure and were positive, though
none reported a consistent clinical illness.
Encephalitis
Meningitis
Guillain-Barré
Syndrome, other
neuropathy or
non-central
myelitis
Dengue*‡
Ilhéus
Japanese encephalitis
Murray Valley
encephalitis
Negishi
Rocio encephalitis
SPH 16111-related
St. Louis encephalitis
Tick-borne
encephalitis
Usutu
Wesselsbron‡
West Nile
Yellow Fever*‡
Zika*‡
Dengue*‡
Modoc
Rio Bravo
Tick-borne
encephalitis
Zika*‡
Dengue*‡
Tick-borne
encephalitis*
West Nile
Zika*‡
Zika virus seems adept at getting into a multitude of
human tissues. It has been identified in blood banked
specimens from asymptomatic patients, saliva of ill
patients and semen in the setting of haematospermia.19–21
The idea, then, that it may cross the placenta is
plausible. A recently published report from an imported
case in Slovenia demonstrated the virus in the brain of
a deceased foetus with microcephaly.22 Additionally,
perinatal assessment of the amniotic fluid of two
foetuses diagnosed with microcephaly by ultrasound in
Brazil also has demonstrated the Zika virus.23 Reports
of human trans-placental infection by Flaviviruses are
sparse but show the potential. Isolated examples of
fetal impact have been demonstrated for West Nile
virus and, more recently, dengue virus infections.24–27
Neurotropism by Flaviviruses is also a known
phenomenon. Table 2 provides examples of various
Flavivirus associations with neurologic disease. Even
among the known encephalitic viruses, host factors
may play a role in whether neuropathic illness develops
from a Flavivirus as well as its severity. These have
included polymorphisms in CCR5, interferon pathways
and toll-like receptor 3 pathways.28 Whether the virus
might be associated with non-neurologic developmental
abnormalities has not yet been fully explored.
The Zika virus infection as both a perinatal infection risk
and potential neurologic hazard is plausible. However,
acknowledging plausibility and declaring causality across
a population are very different acts. From the publically
reported data, assessing the overall severity of the
microcephaly is a challenge let alone ascribing the
presence of the Zika virus in more than the occasional
case. There are myriad infectious and non-infectious
causes of microcephaly. Even if each of the cases had the
presence of the Zika virus, the possibilities that the virus
may be a bystander, enabler for other causations either
from stress, co-infection, toxicities, or even whether the
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© 2016 RCPE
clinical
outbreak in 2013 and early 2014, at a rate among
presented cases of approximately 1%.12–15
*a relatively infrequent clinical manifestation
‡ principal vector for human disease is an Aedes mosquito
mother’s immune response to Zika virus plays a role in
pathogenesis all exist.
Another confounder to understanding is the ever
present threat of observation bias. How well reported
is microcephaly in other circumstances in these
locations? Those data are not evident, though Brazilian
researchers are taking measures to improve these
observations as well as their understanding of what
they might mean.29,30
Nonetheless, this PHEIC declaration is very appropriate.
This rests with the purpose that determining a PHEIC
serves WHO and the global health community. A
PHEIC focuses minds and attention on the threat, in
this instance not Zika virus per se, but the health,
wellness and prospects of vulnerable populations; in
this case women and children in poverty. Reported
microcephaly and other neurologic manifestations
should be investigated and characterised.Those affected
and their communities should be assessed broadly for
their health and social risks. Contributing factors,
infectious and non-infectious, nutritional and
environmental, should be addressed to mitigate
consequences and enhance development.The explosion
and pervasiveness of the Zika virus in these newly
affected areas should draw attention and efforts to
known and novel approaches to targeted mosquito
control. These steps are important not only for the
Zika virus but the continued broad challenges that
5
clinical
DM Brett-Major, CE Roth
dengue, chikungunya and, in some areas, interceding
epidemics of yellow fever virus pose from these same
collections of vulnerabilities and risks.
We should take note of the Zika virus and learn and
act, but focus on the basic lessons to be learned,
applicable to the slate of related risks, and intervene
holistically in those communities that remain vulnerable
and affected by all of them.
Acknowledgments
The authors thank Dr Martyn Bracewell and the
JRCPE’s editorial staff for their critical review and input
on this piece.
References
1 Dick GW, Kitchen SF, Haddow AJ. Zika virus (I). Isolations and
serological specificity. Trans R Soc Trop Med Hyg 1952; 46: 509–20.
2 Dick GW. Zika virus (II). Pathogenicity and physical properties.
Trans R Soc Trop Med Hyg 1952; 46: 521–34.
3 Hennessey M, Fischer M, Staples JE. Zika Virus Spreads to New
Areas – Region of the Americas, May 2015–January 2016. MMWR
Morb Mortal Wkly Rep 2016; 65: 55–8. http://dx.doi.org/10.15585/
mmwr.mm6503e1
4 Duffy MR, Chen TH, Hancock WT et al. Zika virus outbreak on Yap
Island, Federated States of Micronesia. N Engl J Med 2009; 360:
2536–43. http://dx.doi.org/10.1056/NEJMoa0805715
5 World Health Organization. Zika situation report, 19 February 2016.
Emergencies. http://www.who.int/emergencies/zika-virus/situationreport/19-february-2016/en (accessed 22/2/16).
6 Moureau G, Cook S, Lemey P et al. New insights into flavivirus
evolution, taxonomy and biogeographic history, extended by
analysis of canonical and alternative coding sequences. PLoS One
2015; 10: e0117849. http://dx.doi.org/10.1371/journal.
pone.0117849
7 Buathong R, Hermann L, Thaisomboonsuk B et al. Detection of
Zika Virus Infection in Thailand, 2012–2014. Am J Trop Med Hyg
2015; 93: 380–3. http://dx.doi.org/10.4269/ajtmh.15-0022
8 Campos GS, Bandeira AC, Sardi SI. Zika Virus Outbreak, Bahia,
Brazil. Emerg Infect Dis 2015; 21: 1885–6. http://dx.doi.org/10.3201/
eid2110.150847
9 MacNamara FN. Zika virus: a report on three cases of human
infection during an epidemic of jaundice in Nigeria. Trans R Soc Trop
Med Hyg 1954; 48: 139–45.
10 Olson JG, Ksiazek TG, Suhandiman et al. Zika virus, a cause of
fever in Central Java, Indonesia. Trans R Soc Trop Med Hyg 1981; 75:
389–93.
11 Zanluca C, de Melo VC, Mosimann AL et al. First report of
autochthonous transmission of Zika virus in Brazil. Mem Inst
Oswaldo Cruz 2015; 110: 569–72. http://dx.doi.org/10.1590/007402760150192
12 Centre D’Hygiene et de Salubrite Publique. Surveillance de la
dengue et du zika en Polynésie française: Données actualisées au 14
mars 2014. Pape’ete 2014.
13 European Centre for Disease Prevention and Control. Rapid Risk
Assessment: Zika virus infection outbreak, French Polynesia, 14
February 2014. Stockholm: ECDPC. 2014. http://ecdc.europa.eu/
en/publications/Publications/Zika-virus-French-Polynesia-rapidrisk-assessment.pdf (accessed 8/3/16).
14 Cao-Lormeau V-M, Blake A, Mons S et al. Guillain-Barré Syndrome
outbreak associated with Zika virus infection in French Polynesia:
a case-control study. Lancet 2016; Epub ahead of print 29 Feb.
http://dx.doi.org/10.1016/S0140-6736(16)00562-6
15 Smith DW, Mackenzie J. Zika virus and Guillain-Barré syndrome:
another viral cause to add to the list. Lancet 2016; Epub ahead of
print 29 Feb. http://dx.doi.org/10.1016/S0140-6736(16)00564-X
16 Pan American Health Organization. Provisional remarks on Zika virus
infection in pregnant woman: Document for health care professionals.
Montevideo: PAHO/WHO. 25 January 2016. http://iris.paho.org/
xmlui/bitstream/handle/123456789/18600/zikavirus_jan2016.
pdf?sequence=1&isAllowed=y (accessed 8/3/16).
6
17Pan American Health Organization. Epidemiological Alert:
Neurological syndrome, congenital malformations, and Zika virus
infection. Implications for public health in the Americas. Washington
DC: PAHO/WHO. 1 December 2015.
18 European Centre for Disease Prevention and Control. Rapid Risk
Assessment: Microcephaly in Brazil potentially linked to the Zika virus
epidemic, 24 November 2015. Stockholm: ECDPC; 2016. http://
ecdc.europa.eu/en/publications/Publications/zika-microcephalyBrazil-rapid-risk-assessment-Nov-2015.pdf (accessed 8/3/16).
19Musso D, Nhan T, Robin E et al. Potential for Zika virus
transmission through blood transfusion demonstrated during an
outbreak in French Polynesia, November 2013 to February 2014.
Euro Surveill 2014; 19: pii: 20761.
20 Musso D, Roche C, Nhan TX et al. Detection of Zika virus in saliva.
J ClinVirol 2015; 68: 53–5. http://dx.doi.org/10.1016/j.jcv.2015.04.021
21 Musso D, Roche C, Robin E et al. Potential sexual transmission of
Zika virus. Emerg Infect Dis 2015; 21: 359–61. http://dx.doi.
org/10.3201/eid2102.141363
22 Mlakar J, Korva M, Tul N et al. Zika virus associated with
microcephaly. N Engl J Med 2016; Epub ahead of print 10 Feb.
http://dx.doi.org/10.1056/NEJMoa1600651
23 Calvet G, Aguiar RS, Melo AS, et al. Detection and sequencing of
Zika virus from amniotic fluid of fetuses with microcephaly in
Brazil: a case study. Lancet Infect Dis 2016: pii: S1473-3099(16)000955. http://dx.doi.org/10.1016/S1473-3099(16)00095-5
24 Centers for Disease Control and Prevention (CDC). Intrauterine
West Nile virus infection – New York, 2002. MMWR Morb Mortal
Wkly Rep 2002; 51: 1135–6.
25 O’Leary DR, Kuhn S, Kniss KL et al. Birth outcomes following
West Nile Virus infection of pregnant women in the United States:
2003–2004. Pediatrics 2006; 117: e537–45.
26 Nunes PC, Paes MV, de Oliveira CA et al. Detection of dengue
NS1 and NS3 proteins in placenta and umbilical cord in fetal and
maternal death. J Med Virol 2016; Epub ahead of print 21 Jan. http://
dx.doi.org/10.1002/jmv.24479
27 Ribeiro CF, Lopes VG, Brasil P et al. Perinatal transmission of
dengue: a report of 7 cases. J Pediatr 2013; 163: 1514–6. http://
dx.doi.org/10.1016/j.jpeds.2013.06.040
28 Thomas SJ, Endy TP, Rothman AL et al. Flaviviruses (Dengue,Yellow
Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis
Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease,
Alkhurma Hemorrhagic Fever, Zika). In: Bennett JE, Dolin R, Blaser
MJ, editors. Mandell, Douglas and Bennett’s Principles and Practice of
Infectious Diseases. 8th ed. New York: Elsevier Saunders; 2015. p.
1881–1903.e6.
29 Soares de Araújo JS, Regis CT, Gomes RGS et al. Microcephaly in
northeast Brazil: a review of 16 208 births between 2012 and
2015. Bull World Health Organ 2016; Epub ahead of print 4 Feb.
http://dx.doi.org/10.2471/BLT.16.170639
30 Rocha HAL, Correia LL, Leite AJM et al. Microcephaly: normality
parameters and its determinants in northeastern Brazil: a
multicentre prospective cohort study. Bull World Health Organ
2016; Epub ahead of print 8 Feb. http://dx.doi.org/10.2471/
BLT.16.171215
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